Of the impact of the tumor microenvironment on acquired resistance: application note on colorectal cancer and anti-PD1 acquired resistance
Tumor microenvironment and cancer resistance
The tumor microenvironment (TME) is defined by the National Cancer Institute (NCI) as “the normal cells, molecules, and blood vessels that surround and feed a tumor cell. A tumor can change its microenvironment, and the microenvironment can affect how a tumor grows and spreads”[1]. Anderson et al., in 2020, also include the extracellular matrix component in the TME[2], and by citing Truffi et al.,[3] introduce the notion of a dynamic and reciprocal relationship between cancer cells and components of the TME to support cancer cell survival.
The TME has been proven to be linked to the occurrence of tumor resistance[4],[5] by playing a pivotal role in drug (small molecule or biologics) response by fostering immune evasion, altering drug availability, and facilitating cellular crosstalk that ultimately promotes resistance.[6]
Antineo's expertise in resistant models and the tumor microenvironment
Antineo's expertise in the development of secondary resistant oncology in vivo models has been used to investigate the impact of the tumor microenvironment on the occurrence and maintenance of the said resistance.
To this end, C56Bl6 mice have been subcutaneously injected with resistant colorectal cancer murine cells (MC38, part of Antineo's proprietary resistant model catalog), as described in the previous figure. The MC38 cells used are resistant to an immune checkpoint inhibitor, anti-PD1.
After collection of the formed tumor, 2 experimental procedures were performed.
- Direct re-implantation of the sampled tumor, with its whole integrity and tumor microenvironment
- Dissociation of the sampled tumor, collection of the tumor cells (initially resistant) and reimplantation in mice. This procedure destroys and discards the elements of the “natural” microenvironment.
As the results show, the tumor cells reimplanted with the whole microenvironment (procedure 1) have kept the acquired resistance, as they are growing under the anti-PD1 treatment (orange full line) similar to the untreated group (black dashed lines).
After dissociation and loss of the tumor microenvironment, we observe a loss of the resistance of the cancer cells. Indeed, the tumor growth is almost completely inhibited by the anti-PD1 (green full line curve) compared to the dissociated control group (purple dashed line).
These results confirmed the critical role of the tumor microenvironment in the acquired resistance to specific drugs.
Such findings are also valid for in vitro models. When addressing resistance, the presence of the tumor microenvironment has to be recapitulated. In this case, tumoroids are the best option. To this extend, Antineo's 3D bioprinting tumoroids are specifically engineered to mimic the original tumor microenvironment as best as possible to provide an exploitable dataset to our customer.
Why does TME matter in drug development?
Schulze and Ringel made a meta-analysis on the market value taken in the case of a first-in-class or best-in-class[7]. In both cases, drug developers have a strong incentive, from the market itself, but also from the healthcare systems to bring added value with a new drug market launch.
This added value, in oncology, is either fewer side effects or in most cases, less relapse after remission of the primary tumor. This means developing a drug or combination that can act and treat resistant tumors is the key to market success.
Having access to not only cancer cells, but the recapitulation of the tumor in its whole complexity is key to accelerate and optimize the development of the most promising drug candidate, and future best/first in class
